Cristina Saura1, Jose A Garcia-Saenz2, Binghe Xu2, Wael Harb2, Rebecca Moroose2, Timothy Pluard2, Javier Cortés2, Corinne Kiger2, Caroline Germa2, Kongming Wang2, Miguel Martin2, José Baselga2, Sung-Bae Kim2. 1. Cristina Saura and Javier Cortés, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona; Jose A. Garcia-Saenz, Hospital Clinico San Carlos; Miguel Martin, Hospital Gregorio Maranon, Universidad Complutense, Madrid, Spain; Binghe Xu, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; Wael Harb, Horizon Medical Group, Lafayette, IN; Rebecca Moroose, University of Florida Health Cancer Center, Orlando, FL; Timothy Pluard, Washington University School of Medicine, St Louis, MO; Corinne Kiger, Pfizer Global Research and Development, Paris; Caroline Germa, Novartis Pharma, Rueil-Malmaison, France; Kongming Wang, Pfizer, Pearl River; José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; and Sung-Bae Kim, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. csaura@vhio.net. 2. Cristina Saura and Javier Cortés, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona; Jose A. Garcia-Saenz, Hospital Clinico San Carlos; Miguel Martin, Hospital Gregorio Maranon, Universidad Complutense, Madrid, Spain; Binghe Xu, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; Wael Harb, Horizon Medical Group, Lafayette, IN; Rebecca Moroose, University of Florida Health Cancer Center, Orlando, FL; Timothy Pluard, Washington University School of Medicine, St Louis, MO; Corinne Kiger, Pfizer Global Research and Development, Paris; Caroline Germa, Novartis Pharma, Rueil-Malmaison, France; Kongming Wang, Pfizer, Pearl River; José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; and Sung-Bae Kim, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Abstract
PURPOSE: Neratinib is a potent irreversible pan-tyrosine kinase inhibitor with antitumor activity and acceptable tolerability in patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer. A multinational, open-label, phase I/II trial was conducted to determine the maximum-tolerated dose (MTD) of neratinib plus capecitabine in patients with solid tumors (part one) and to evaluate the safety and efficacy of neratinib plus capecitabine in patients with HER2-positive metastatic breast cancer (part two). PATIENTS AND METHODS: Part one was a 3 + 3 dose-escalation study in which patients with advanced solid tumors received oral neratinib once per day continuously plus capecitabine twice per day on days 1 to 14 of a 21-day cycle at predefined dose levels. In part two, patients with trastuzumab-pretreated HER2-positive metastatic breast cancer received neratinib plus capecitabine at the MTD. The primary end point in part two was objective response rate (ORR). RESULTS: In part one (n = 33), the combination of neratinib 240 mg per day plus capecitabine 1,500 mg/m(2) per day was defined as the MTD, which was further evaluated in part 2 (n = 72). The most common drug-related adverse events were diarrhea (88%) and palmar-plantar erythrodysesthesia syndrome (48%). In part two, the ORR was 64% (n = 39 of 61) in patients with no prior lapatinib exposure and 57% (n = 4 of 7) in patients previously treated with lapatinib. Median progression-free survival was 40.3 and 35.9 weeks, respectively. CONCLUSION: Neratinib in combination with capecitabine had a manageable toxicity profile and showed promising antitumor activity in patients with HER2-positive metastatic breast cancer pretreated with trastuzumab and lapatinib.
PURPOSE:Neratinib is a potent irreversible pan-tyrosine kinase inhibitor with antitumor activity and acceptable tolerability in patients with humanepidermal growth factor receptor 2 (HER2) -positive breast cancer. A multinational, open-label, phase I/II trial was conducted to determine the maximum-tolerated dose (MTD) of neratinib plus capecitabine in patients with solid tumors (part one) and to evaluate the safety and efficacy of neratinib plus capecitabine in patients with HER2-positive metastatic breast cancer (part two). PATIENTS AND METHODS: Part one was a 3 + 3 dose-escalation study in which patients with advanced solid tumors received oral neratinib once per day continuously plus capecitabine twice per day on days 1 to 14 of a 21-day cycle at predefined dose levels. In part two, patients with trastuzumab-pretreated HER2-positive metastatic breast cancer received neratinib plus capecitabine at the MTD. The primary end point in part two was objective response rate (ORR). RESULTS: In part one (n = 33), the combination of neratinib 240 mg per day plus capecitabine 1,500 mg/m(2) per day was defined as the MTD, which was further evaluated in part 2 (n = 72). The most common drug-related adverse events were diarrhea (88%) and palmar-plantar erythrodysesthesia syndrome (48%). In part two, the ORR was 64% (n = 39 of 61) in patients with no prior lapatinib exposure and 57% (n = 4 of 7) in patients previously treated with lapatinib. Median progression-free survival was 40.3 and 35.9 weeks, respectively. CONCLUSION:Neratinib in combination with capecitabine had a manageable toxicity profile and showed promising antitumor activity in patients with HER2-positive metastatic breast cancer pretreated with trastuzumab and lapatinib.
Authors: John W Park; Minetta C Liu; Douglas Yee; Christina Yau; Laura J van 't Veer; W Fraser Symmans; Melissa Paoloni; Jane Perlmutter; Nola M Hylton; Michael Hogarth; Angela DeMichele; Meredith B Buxton; A Jo Chien; Anne M Wallace; Judy C Boughey; Tufia C Haddad; Stephen Y Chui; Kathleen A Kemmer; Henry G Kaplan; Claudine Isaacs; Rita Nanda; Debasish Tripathy; Kathy S Albain; Kirsten K Edmiston; Anthony D Elias; Donald W Northfelt; Lajos Pusztai; Stacy L Moulder; Julie E Lang; Rebecca K Viscusi; David M Euhus; Barbara B Haley; Qamar J Khan; William C Wood; Michelle Melisko; Richard Schwab; Teresa Helsten; Julia Lyandres; Sarah E Davis; Gillian L Hirst; Ashish Sanil; Laura J Esserman; Donald A Berry Journal: N Engl J Med Date: 2016-07-07 Impact factor: 91.245
Authors: S P Corona; N Sobhani; A Ianza; G Roviello; G Mustacchi; M Bortul; F Zanconati; D Generali Journal: Med Oncol Date: 2017-05-19 Impact factor: 3.064
Authors: Mariana Segovia-Mendoza; María E González-González; David Barrera; Lorenza Díaz; Rocío García-Becerra Journal: Am J Cancer Res Date: 2015-08-15 Impact factor: 6.166